White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear 1,2 . Here we retrospectively categorized 134,529 18 F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values.

Preeclampsia (PE) is a disorder of pregnancy that manifests as late gestational maternal hypertension and proteinuria and can be life-threatening to both the mother and baby. It is believed that abnormal placentation is responsible for the cascade of events leading to the maternal syndrome. Embryo implantation is critical to establishing a healthy pregnancy. Defective implantation can cause adverse “ripple effects,” leading to abnormal decidualization and placentation, retarded fetal development, and poor pregnancy outcomes, such as PE and fetal growth restriction. The precise mechanism(s) of implantation defects that lead to PE remain elusive. BPH/5 mice, which spontaneously develop the cardinal features of PE, show peri-implantation defects including upregulation of Cox2 and IL-15 at the maternal-fetal interface. This was associated with decreased decidual natural killer (dNK) cells, which have important roles in establishing placental perfusion. Interestingly, a single administration of a Cox2 inhibitor (celecoxib) during decidualization restrained Cox2 and IL-15 expression, restored dNK cell numbers, improved fetal growth, and attenuated late gestational hypertension in BPH/5 female mice. This study provides evidence that decidual overexpression of Cox2 and IL-15 may trigger the adverse pregnancy outcomes reflected in the preeclamptic syndrome, underscoring the idea that Cox2 inhibitor treatment is an effective strategy for the prevention of PE-associated fetal and maternal morbidity and mortality.

Preeclampsia (PE) is a devastating disorder of pregnancy that classically presents with maternal hypertension and proteinuria after 20 wk of gestation. In addition to being a leading cause of maternal and fetal morbidity/mortality, epidemiological and prospective studies have revealed long-term consequences for both the mother and baby of preeclamptic pregnancies, including chronic hypertension as well as other cardiovascular diseases and metabolic derangements. To better understand the effect of in utero exposure of PE on offspring, we utilized the BPH/5 mouse, a spontaneous model of the maternal and fetal PE syndrome. We hypothesized that young BPH/5 offspring would have altered metabolic and cardiovascular phenotypes. Indeed, BPH/5 growth-restricted offspring showed excess catch-up growth by early adulthood due to hyperphagia and increased white adipose tissue (WAT) accumulation, with inflammation markers isolated to the reproductive WAT depot only. Both excessive WAT accumulation and the inflammatory WAT phenotype were corrected by pair-feeding young BPH/5 female mice. We also found that young BPH/5 female mice showed evidence of leptin resistance. Indeed, chronic hyperleptinemia has been shown to characterize other rodent models of PE; however, the maternal metabolic profile before pregnancy has not been fully understood. Furthermore, we found that these mice show signs of cardiovascular anomalies (hypertension and cardiomegaly) and altered signaling within the reproductive axis in early life. Future studies will involve challenging the physiological metabolic state of BPH/5 mice through pair-feeding to reduce WAT before pregnancy and determining its causal role in adverse pregnancy outcomes.

In the central nervous system, angiotensin II (AngII) binds to angiotensin type 1 receptors (AT1R) to affect autonomic and endocrine functions as well as learning and memory. However, understanding the function of cells containing AT1Rs has been restricted by limited availability of specific antisera, difficulties discriminating AT1 receptor-immunoreactive cells in many brain regions and, the identification of AT1R-containing neurons for physiological and molecular studies. Here, we demonstrate that an Agtr1a bacterial artificial chromosome (BAC) transgenic mouse line that expresses type A AT1Rs (AT1aRs) identified by enhanced green fluorescent protein (EGFP) overcomes these shortcomings. Throughout the brain, AT1aR-EGFP was detected in the nuclei and cytoplasm of cells, most of which were neurons. EGFP often extended into dendritic processes and could be identified either natively or with immunolabeling of EGFP. The distribution of AT1aR-EGFP cells in brain closely corresponded to that reported for AngII binding and AT1aR protein and mRNA. In particular, AT1aR-EGFP cells were in autonomic regions (e.g., hypothalamic paraventricular nucleus, central nucleus of the amygdala, parabrachial nucleus, nuclei of the solitary tract and rostral ventrolateral medulla) and in regions involved in electrolyte and fluid balance (i.e., subfornical organ) and learning and memory (i.e., cerebral cortex and hippocampus). Additionally, dual label electron microscopic studies in select brain areas demonstrate that cells containing AT1aR-EGFP colocalize with AT1R-immunoreactivity. Assessment of AngII-induced free radical production in isolated EGFP cells demonstrated feasibility of studies investigating AT1aR signaling ex vivo. These findings support the utility of Agtr1a BAC transgenic reporter mice for future studies understanding the role of AT1 receptor containing cells in brain function.

Rationale: Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases. Objective: We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. Key Words: heart Ⅲ reactive oxygen species Ⅲ NADPH oxidase Ⅲ brain Ⅲ sympathetic nerves D espite recent decline in the incidence of many cardiovascular diseases in the United States, that of heart failure (HF) continues to rise. 1 HF is characterized by progressively deteriorating cardiac function, in part because of persistent sympathetic overactivation that is initiated in response to impaired cardiac function. 2 Whereas increased sympathetic drive aids perfusion acutely following a cardiac insult such as myocardial infarction (MI), chronic sympathoexcitation contributes to fluid retention, as well as cardiac arrhythmias, hypertrophy, and apoptosis, all of which contribute to declining cardiac function over time. 2 The paraventricular nucleus (PVN) of the hypothalamus is a critical site of autonomic and neuroendocrine regulation. 3 The nucleus of the tractus solitarius (NTS) relays afferent information to the PVN, which, in turn, sends efferent projections to the rostral ventral lateral medulla (RVLM) and spinal cord to modulate sympathetic outflow. 4 Neurons of the forebrain circumventricular subfornical organ (SFO) (a structure outside the blood-brain barrier that interacts with peripheral circulating factors) also project to the PVN, which can further stimulate sympathoexcitation as well as the production and secretion of vasopressin. 3,4 Indeed, the PVN is strongly implicated in the neurohumoral dysregulation observed in HF. 5 Recently, our studies in mice showed that PVN neurons are chronically activated after MI, and that this parallels the sustained elevations in sympathetic outflow during MI-induced HF. 6 Substantial evidence implicates reactive oxygen species (ROS) as key signaling molecules in PVN and other central nervous system (CNS) nuclei in maintaining cardiovascular homeostasis 7,8 and in mediating cardiovascular diseases such as hypertension and HF. 6,9,10 For example, increased redox signaling has been observed in SFO and RVLM in animal models of HF, and this parallels rising sympathetic outflow. 6,10,11 Similarly, afferent reflexes involving neuronal signaling from the NTS to the PVN, 12 a pathway that relies on ROS formation in the PVN under normal conditions, 13,14 are elevated during HF. 15,16 Abundant evidence implicates the NADPH oxidase (Nox) family of enzymes as a key s...